National Highway 221 starts at the junction with National Highway 9 near Vijayawada and runs north through Kondapalli, Tiruvuru, Kottagudam, Bhadrachalam and Nellipaka before entering Chhattisgarh past Chinturu. The highway is 155 km-long in Andhra Pradesh.

In Chhattisgarh, Konta is the first major settlement that lies along the National Highway 221. It then passes north-east through Penta, Sukma, Darba and
Sosanpal before terminating at the junction with National Highway 16 near Jagdalpur. National Highway 221 has a total length of 155 km in Chhattisgarh.